A bifunctional molecule that displays context-dependent cellular activity

被引:41
作者
Braun, PD
Barglow, KT
Lin, YM
Akompong, T
Briesewitz, R
Ray, GT
Haldar, K
Wandless, TJ [1 ]
机构
[1] Stanford Univ, Dept Chem, Stanford, CA 94305 USA
[2] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
[3] Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA
[4] Northwestern Univ, Sch Med, Dept Microbiol, Chicago, IL 60611 USA
[5] Northwestern Univ, Sch Med, Dept Immunol, Chicago, IL 60611 USA
关键词
D O I
10.1021/ja035176q
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The cell-permeable dihydrofolate reductase inhibitor methotrexate was covalently linked to a ligand for the protein FKBP to create a bifunctional molecule called MTXSLF. The covalent tether between the two ligands was designed to be prohibitively short, so that unfavorable protein-protein interactions between DHFR and FKBP preclude formation of a trimeric complex. In vitro and in vivo experiments demonstrate that MTXSLF is an effective inhibitor of human DHFR, but that efficacy is decreased in the presence of human FKBP due to the high concentration of FKBP and its tight affinity for MTXSLF. MTXSLF also inhibits Plasmodium falciparum DHFR in vitro, but a low concentration of the weaker binding Plasmodium FKBP has no effect on the inhibitory potency of MTXSLF in vivo. These studies illustrate a potentially general strategy for modulating the biological activity of synthetic molecules that depends on the ligand-binding properties of a nontarget protein.
引用
收藏
页码:7575 / 7580
页数:6
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